Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

Objective To compare the dosimetric differences in volumetric modulated arc therapy(VMAT)for pediatric Wilms'tumor under flattening filter(FF)and flattening filter free(FFF)modes.Methods Ten children with Wilms'tumor who received radiotherapy at some hospital from August 2022 to October 2023 were selected retrospectively,for whom the VMAT plans were designed under FF and FFF modes.The two kinds of plans were compared in terms of planning target volume(PTV)dosimetric parameters,exposure dose to organ at risk(OAR),monitor units,gamma pass rate and treatment time.Results The FFF plan behaved significantly better than the FF plan in D2,D98 and HI(P＜0.05);the two kinds of plans had no statistically obvious differences in D50 and CI(P＞0.05).The FFF plan gained advantages over the FF plan in Dmean,V5 and V10 of the contralateral kidney,Dmean,V5 and V10 of the liver and Dmax of the spinal cord,and the differences were statistically significant(P＜0.05).The FF plan outperformed the FFF plan in gamma pass rate and monitor units,while the FFF plan had the treatment time shorter than that of the FF plan,and the differences were statistically significant(P＜0.05).The two kinds of VMAT plans both had the gamma pass rates higher than 95％.Conclusion The VMAT plans under both FF and FFF modes meet clinical treatment requirements,and the FFF mode has advantages over the FF mode in terms of PTV dose distribution,exposure dose to OAR and treatment time,which contribute to enhancing the treatment outcome and cooperation of the children.[Chinese Medical Equipment Journal,2024,45(4):70-73]

BACKGROUND: Stress cardiomyopathy (SCM) currently has a high incidence in older adults, and the theories regarding its causes include "catecholamine myocardial toxicity" and "sympathetic hyperactivation". However, the role of the central nervous system in the pathogenesis of SCM remains unknown. We investigated the role of microglia activation in the paraventricular hypothalamic nucleus (PVN) in the development of SCM. METHODS: An SCM model was created using male Sprague-Dawley (SD) rats, immobilized for 6 h every day for a week. Electrocardiogram, cardiac electrophysiology, and echocardiography examinations were performed to verify the changes in cardiac structure and function in rats with SCM. RNA sequencing was used to explore the changes in the hypothalamus during SCM. In addition, brain and heart tissues were collected to detect microglial activation and sympathetic activity. RESULTS: The main findings were as follows: (1) immobilization stress successfully induced SCM in SD rats; (2) microglia were significantly activated in the hypothalamus, as evidenced by cytosol thickening, increases in the number of microglial branches, and microglia enriched in the PVN; (3) in SCM, the microglia in the PVN exhibited increased central and peripheral cardiac sympathetic activity and increased the expression of neuroinflammatory factors; and (4) it is possible that inhibiting microglial activation could suppress the sympathetic activity of the central nervous system and heart and increase cardiac electrical stability in SCM rats. CONCLUSIONS SCM was induced in SD rats by immobilization stress, acting through the activation of the hypothalamic microglia. The activated microglia were specifically enriched in the PVN, increasing the activity of the central and peripheral sympathetic nervous systems by regulating the expression of neuro-inflammatory factors, mediating dysfunction of the left ventricle, and increasing the susceptibility to ventricular arrhythmias.

ObjectiveTo analyze the clinical outcomes of Gardner stage I and stage Ⅱ fresh blastocysts transfer on day 5 in patients without transferable cleavage-stage embryos， so as to explore the best transfer strategy. MethodsA retrospective analysis was done on patients without transferable cleavage-stage embryos who underwent single blastocyst transfer in our IVF center from January 2014 to December 2019. Of the total of 178 cycles of fresh blastocyst transfer， 97 involved stage I and 81 stage Ⅱ. Control Group 1 included 754 cycles of fresh grade 2 cleavage-stage embryo transfer on day 3 and Control Group 2 included 144 transfer of day-6 vitrified blastocysts. Like study groups， two control groups were also single blastocyst or single embryo transfer cycles. The clinical outcomes including live birth rate， clinical pregnancy rate， early miscarriage rate and ongoing pregnancy rate， and neonatal conditions such as gestational week at delivery， neonatal weight and length were analyzed among the groups. ResultsThe live birth rate （7.22% vs. 18.83%/7.22% vs. 15.97%）， clinical pregnancy rate （11.34% vs. 25.33%/11.34% vs. 24.31%） and ongoing pregnancy rate （7.22% vs. 19.89%/7.22% vs. 15.97%） were significantly decreased in fresh stage I blastocyst transfer group than those in Control Group 1 （P < 0.01） and Control Group 2 （P < 0.05）. There was no significant difference in early miscarriage rate and neonatal conditions between fresh stage I blastocyst transfer group and Control Group 1 or between fresh stage I blastocyst transfer group and Control Group 2 （all P > 0.05）. There was no significant difference in clinical outcomes and neonatal conditions between fresh stage Ⅱ blastocyst transfer group and Control Group 1 or between fresh stage Ⅱ blastocyst transfer group and Control Group 2 （all P > 0.05）. ConclusionIn patients without transferable cleavage-stage embryos， all embryos are better to be cultured to blastocyte-stage. Higher clinical pregnancy rate and live birth rate could be achieved if stage I blastocysts on D5 is transferred in a subsequent thawed-cycles after extended culture and stage Ⅱ blastocysts on D5 is transferred in fresh cycles.

Discoid meniscus injury is a kind of common sports injury. Its treatment methods include arthroscopic discoid meniscus plasty, discoid meniscus subtotal resection, discoid meniscus total resection and so on. Although the short-term clinical effect is good, the long-term clinical effect is not ideal. At present, different scholars have different views on the choice of surgical methods for discoid meniscus injury. In recent years, many scholars have shown that the choice of operation and the change of lower limb force line are related to the therapeutic effect of discoid meniscus injury. This paper mainly summarizes the current situation of the treatment of discoid meniscus injury and the changes of the force line of the lower limbs after operation, and expounds therole of the evaluation of the force line of the lower limbs in the treatment of discoid meniscus, so as to provide the basis for the clinical individualized treatment of discoid meniscus injury.
Arthroscopy ; Humans ; Knee Joint ; Lower Extremity ; Menisci, Tibial ; Tibial Meniscus Injuries

OBJECTIVE: To explore risk factors of the periprosthetic fracture after hip arthroplasty. METHODS: Potential studies were searched in databases including Pubmed, Embase, Cochrane Library, CNKI as well as Wanfang Database up to November 2018 and references in related literatures. The methodological quality of literature was estimated by Newcastle-Ottawa Scale. Raw data were merged and tested mainly by Revmain 5.3. RESULTS: Seventeen studies in total were appropriate with 90 632 patients. The results revealed that it increased the risk of periprosthetic fracture after hip arthroplasty, including female (=1.62, 95%CI:1.44 to 1.82, <0.01), revision(=3.78, 95%CI:1.88 to 7.58, <0.01), preoperative diagnosis of rheumatoid arthritis(=1.60, 95%CI:1.07 to 2.37, =0.02). Conversely, patients involved with cemented prosthesis fixation(=0.43, 95%CI:0.27 to 0.68, <0.01) were less likely to suffer periprosthetic fracture after hip arthroplasty. Other factors were not significantly relevant to periprosthetic fracture after hip arthroplasty, including the age, preoperative diagnosis(femoral head necrosis, osteoarthritis, developmental dysplasia of the hip, femoral fracture, concomitant heart diseases) and American Society of Anesthesiologists >=3. CONCLUSIONS Orthopedics doctors should constantly be cantious about the risk factors including female, revision and diagnosis of rheumatoid arthritis. They are supposed to prevent the periprosthetic fracture by gentle operation during hip arthroplasty and monitoring the functional exercise after operations when the above risk factors occur.
Arthroplasty, Replacement, Hip ; Female ; Femoral Fractures ; Humans ; Periprosthetic Fractures ; Reoperation ; Risk Factors

BACKGROUND/AIMS: There are increasing evidences for gastrointestinal motility disorder (GIMD) and gastric stress ulcer induced by noise stress. The present study was to investigate the reversed effect of melatonin on GIMD and gastric stress ulcer induced by noise stress and potential mechanism. METHODS: Noise stress was induced on rats, and melatonin (15 mg/kg) was administered to rats by intraperitoneal injection. Differences were assessed in gastric residual rate (GRR), small intestine propulsion rate (SPR), Guth injury score, cortisol, gastrointestinal hormones (calcitonin-gene-related peptide and motilin) and oxidative stress markers (superoxide dismutase and malondialde hyde) in blood plasma as well as gastric mucosa homogenate with or without melatonin. The pathological examination of gastric mucosa was also performed. RESULTS: The GRR and SPR were improved by noise stress compared with control (P < 0.05). The pathological examination and Guth injury score revealed gastric stress ulcer. Moreover, the levels of cortisol, motilin and malondialdehyde in blood plasma and malondialdehyde in gastric mucosa homogenate were increased by noise stress (P < 0.05). CGRP and superoxide dismutase activity in both of blood plasma and gastric mucosa homogenate were significantly decreased (P< 0.05). Furthermore, melatonin reversed changes in GRR, SPR, pathological examination, Guth injury score, cortisol, motilin, CGRP, superoxide dismutase activity and malondialdehyde (P < 0.05). CONCLUSIONS: Melatonin is effective in reversing the GIMD and gastric stress ulcer induced by noise stress. The underlying mechanism may be involved in oxidative stress and gastrointestinal hormones.
Animals ; Gastric Mucosa ; Gastrointestinal Hormones* ; Gastrointestinal Motility* ; Hydrocortisone ; Injections, Intraperitoneal ; Intestine, Small ; Malondialdehyde ; Melatonin* ; Motilin ; Noise* ; Oxidative Stress* ; Plasma ; Rats* ; Superoxide Dismutase ; Ulcer*

BACKGROUNDNeuroblastoma (NB) is one of the most common malignant solid tumors of childhood. It is still not clear whether the apoptosis of tumor cells or the non-tumor cells contributes to the increase of concentration of cytochrome c (Cyt c) in the serum of the cancer patients. The aim of this research was to identify the source of the Cyt c in the serum when the tumor grows up by subcutaneous inoculation of human NB cells into nude mice.

METHODSWe subcutaneously inoculated human NB cells (KP-N-NS) into nude mice and collected the sera of tumor-bearing mice (n = 14) and control mice (n = 25) 4 weeks later in order to screen for and identify differentially expressed proteins in the serum. Differentially expressed proteins in the serum were screened by surface-enhanced laser desorption/ionization-time-of-flight (SELDI-TOF) mass spectrometry.

RESULTSThe relative intensity of a protein having a mass-to-charge ratio (m/z) of 11 609 was 3338.37 ± 3410.85 in the tumor group and 59.84 ± 40.74 in the control group, indicating that the expression level of this protein in the tumor group was 55.8 times higher than that in the control group. Serum proteins were separated and purified by high-performance liquid chromatography (HPLC). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to produce peptide mass fingerprints (PMFs). Spectrum analysis and a database search revealed that the highly expressed protein (m/z = 11 605.4) from the serum of tumor-bearing mice was the mouse Cyt c.

CONCLUSIONSIncreased concentration of Cyt c in the serum of tumor-bearing nude mice might be partially attributed to the secretion of this protein by non-tumor cells.

Animals ; Apoptosis ; physiology ; Cell Line, Tumor ; Chromatography, High Pressure Liquid ; Cytochromes c ; blood ; Female ; Humans ; Mice ; Mice, Nude ; Neuroblastoma ; blood ; Tandem Mass Spectrometry ; Xenograft Model Antitumor Assays

BACKGROUNDRecent studies have identified signal transducer and activator of transcription 4 (STAT4) as a susceptibility gene for systemic lupus erythematosus (SLE) in different populations. In order to examine whether the allele distribution of the single nucleotide polymorphism (SNP) in gene STAT4 rs7574865 in patients with SLE is different from those of healthy controls in Chinese Northern Han population, we investigated whether the variants of STAT4 rs7574865 were associated with any specific clinical features of SLE.

METHODSWe genotyped SNPs in STAT4 rs7574865 in 252 patients with SLE and 497 healthy controls. All subjects were from the Northern part of Chinese Han population. The genotypes in rs7574865 were determined by polymerase chain reaction (PCR) and consequence direct sequencing of PCR products in the DNA samples.

RESULTSThere was a significant difference in distribution of the SNPs in rs7574865 between the SLE patients and healthy controls. Compared with healthy controls, there was a significant correlation between TT genotypes in rs7574865 and the risk of SLE when GG genotype was used as a reference genotype after adjusting for gender and age. The frequency of T allele in the SLE patients was strongly significantly higher than that of healthy controls. Furthermore, there was a significant difference in the distribution of SNP in rs7574865 between male and female SLE patients, when compared with healthy controls. The frequency of T allele in rs7574865 in male patients was significantly higher than that of male healthy controls or female patients. There was no significant correlation between the frequencies of T allele in STAT4 rs7574865 and the clinical features of SLE.

CONCLUSIONSThe SNP rs7574865 in STAT4 is strongly associated with risk of SLE in the Chinese Northern Han population. The TT genotype and T allele in STAT4 rs7574869 are susceptibility factors for SLE, especially for male SLE patients.

Adult ; Asian Continental Ancestry Group ; genetics ; Female ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Linkage Disequilibrium ; genetics ; Lupus Erythematosus, Systemic ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; STAT4 Transcription Factor ; genetics ; Young Adult